A mechanistic roadmap for the clinical application of cardiac cell therapies


The development of cells for regenerative therapy has encountered many pitfalls on its path to clinical translation. In cardiology, clinical studies of heart-targeted cell therapies began two decades ago, yet progress towards reaching an approved product has been slow. In this Perspective, I provide an overview of recent cardiac cell therapies, with a focus on the hurdles limiting the translation of cell products from research laboratories to clinical practice. By focusing on heart failure as a target indication, I argue that strategies for overcoming limitations in clinical translation require an increasing emphasis on mechanism-supported efficacy, rather than on phenomenological observations. As research progresses from cells to paracrine mechanisms to defined factors, identifying those defined factors that are involved in achieving superior therapeutic efficacy will better inform the use of cells as therapeutic candidates. The next generation of cell-free biologics may provide the benefits of cell therapy without the intrinsic limitations of whole-cell products.

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Fig. 1: Biological processes modulated by cell therapy.
Fig. 2: Clinical testing of cell therapies for heart disease.
Fig. 3: Obstacles in the translation of cell therapy, from proof of concept through to product approval.
Fig. 4: CDC properties.
Fig. 5: Changes from canonical to indirect (paracrine) mechanisms of action of cell therapy.
Fig. 6: Exosome biology and evidence of exosome efficacy.
Fig. 7: Defined exosome contents implicated in CDC-mediated cardioprotection.


  1. 1.

    Roth, G. A. et al. Global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015. J. Am. Coll. Cardiol. 70, 1–25 (2017).

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    Eschenhagen, T. et al. Cardiomyocyte regeneration: a consensus statement. Circulation 136, 680–686 (2017).

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Marinescu, K. K., Uriel, N., Mann, D. L. & Burkhoff, D. Left ventricular assist device-induced reverse remodeling: it’s not just about myocardial recovery. Expert Rev. Med. Devices 14, 15–26 (2017).

    CAS  PubMed  Google Scholar 

  4. 4.

    Menasche, P. et al. Autologous skeletal myoblast transplantation for cardiac insufficiency. First Clin. Case. Arch. Mal. Coeur. Vaiss. 94, 180–182 (2001).

    CAS  Google Scholar 

  5. 5.

    Voronov, R. A. Experimental study of the regenerative potentialities of the cardiac and somatic musculatures. Arkh. Anat. Gistol. Embriol. 69, 35–40 (1975).

    CAS  PubMed  Google Scholar 

  6. 6.

    Koh, G. Y., Klug, M. G., Soonpaa, M. H. & Field, L. J. Differentiation and long-term survival of C2C12 myoblast grafts in heart. J. Clin. Invest. 92, 1548–1554 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Taylor, D. A. et al. Regenerating functional myocardium: improved performance after skeletal myoblast transplantation. Nat. Med. 4, 929–933 (1998).

    CAS  PubMed  Google Scholar 

  8. 8.

    Menasche, P. et al. The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation. Circulation 117, 1189–1200 (2008).

    PubMed  Google Scholar 

  9. 9.

    Orlic, D. et al. Bone marrow cells regenerate infarcted myocardium. Nature 410, 701–705 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Chien, K. R. Stem cells: lost in translation. Nature 428, 607–608 (2004).

    CAS  PubMed  Google Scholar 

  11. 11.

    Strauer, B. E. et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 106, 1913–1918 (2002).

    PubMed  Google Scholar 

  12. 12.

    Fisher, S. A., Doree, C., Mathur, A., Taggart, D. P. & Martin-Rendon, E. Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. Cochrane Database Syst. Rev. 12, CD007888 (2016).

    PubMed  Google Scholar 

  13. 13.

    Mathur, A. et al. The consensus of the Task Force of the European Society of Cardiology concerning the clinical investigation of the use of autologous adult stem cells for the treatment of acute myocardial infarction and heart failure: update 2016. Eur. Heart J. 38, 2930–2935 (2017).

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    Jeevanantham, V., Afzal, M. R., Zuba-Surma, E. K. & Dawn, B. Clinical trials of cardiac repair with adult bone marrow-derived cells. Methods Mol. Biol. 1036, 179–205 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Nowbar, A. N. et al. Discrepancies in autologous bone marrow stem cell trials and enhancement of ejection fraction (DAMASCENE): weighted regression and meta-analysis. BMJ 348, g2688 (2014).

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Wang, L. T. et al. Human mesenchymal stem cells (MSCs) for treatment towards immune- and inflammation-mediated diseases: review of current clinical trials. J. Biomed. Sci. 23, 76 (2016).

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Behfar, A. et al. Guided stem cell cardiopoiesis: discovery and translation. J. Mol. Cell. Cardiol. 45, 523–529 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Psaltis, P. J. et al. Enrichment for STRO-1 expression enhances the cardiovascular paracrine activity of human bone marrow-derived mesenchymal cell populations. J. Cell. Physiol. 223, 530–540 (2010).

    CAS  PubMed  Google Scholar 

  19. 19.

    Golpanian, S., Wolf, A., Hatzistergos, K. E. & Hare, J. M. Rebuilding the damaged heart: mesenchymal stem cells, cell-based therapy, and engineered heart tissue. Physiol. Rev. 96, 1127–1168 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Bartunek, J. et al. Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial design. Eur. J. Heart Fail. 18, 160–168 (2016).

    PubMed  Google Scholar 

  21. 21.

    Perin, E. C. et al. A phase II dose-escalation study of allogeneic mesenchymal precursor cells in patients with ischemic or nonischemic heart failure. Circ. Res. 117, 576–584 (2015).

    CAS  PubMed  Google Scholar 

  22. 22.

    Povsic, T. J. et al. The RENEW trial: efficacy and safety of intramyocardial autologous CD34+ cell administration in patients with refractory angina. JACC Cardiovasc. Interv. 9, 1576–1585 (2016).

    PubMed  Google Scholar 

  23. 23.

    Beltrami, A. P. et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114, 763–776 (2003).

    CAS  PubMed  Google Scholar 

  24. 24.

    Bolli, R. et al. Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet 378, 1847–1857 (2011).

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    van Berlo, J. H. et al. c-kit+ cells minimally contribute cardiomyocytes to the heart. Nature 509, 337–341 (2014).

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    The Lancet Editors. Expression of concern: the SCIPIO trial. Lancet 383, 1279 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Chong, J. J. et al. Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. Nature 510, 273–277 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Shiba, Y. et al. Allogeneic transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts. Nature 538, 388–391 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Menasche, P. et al. Transplantation of human embryonic stem cell-derived cardiovascular progenitors for severe ischemic left ventricular dysfunction. J. Am. Coll. Cardiol. 71, 429–438 (2018).

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Menasche, P. The future of stem cells: should we keep the “stem” and skip the “cells”? J. Thorac. Cardiovasc. Surg. 152, 345–349 (2016).

    PubMed  Google Scholar 

  32. 32.

    The Editor. A futile cycle in cell therapy. Nat. Biotechnol. 35, 291 (2017).

    Google Scholar 

  33. 33.

    Bolli, R. Repeated cell therapy: a paradigm shift whose time has come. Circ. Res. 120, 1072–1074 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Tompkins, B. A., Natsumeda, M., Balkan, W. & Hare, J. M. What is the future of cell-based therapy for acute myocardial infarction. Circ. Res. 120, 252–255 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Quyyumi, A. A. et al. PreSERVE-AMI: a randomized, double-blind, placebo-controlled clinical trial of intracoronary administration of autologous CD34+ cells in patients with left ventricular dysfunction post STEMI. Circ. Res. 120, 324–331 (2017).

    CAS  PubMed  Google Scholar 

  36. 36.

    Zwetsloot, P. P. et al. Cardiac stem cell treatment in myocardial infarction: a systematic review and meta-analysis of preclinical studies. Circ. Res. 118, 1223–1232 (2016).

    CAS  PubMed  Google Scholar 

  37. 37.

    Dodson, B. P. & Levine, A. D. Challenges in the translation and commercialization of cell therapies. BMC Biotechnol. 15, 70 (2015).

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Campbell, A. et al. Concise review: process development considerations for cell therapy. Stem Cells Transl. Med 4, 1155–1163 (2015).

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    Karnieli, O. Cell therapy: early process development and optimization of the manufacturing process are critical to ensure viability of the product, quality, consistency and cost efficiency. J. Commer. Biotechnol. https://doi.org/10.5912/jcb695 (2015).

  40. 40.

    Szymczak, M. M., Friedman, R. L., Uppoor, R. & Yacobi, A. Detection, measurement, and control in pharma manufacturing. Pharm. Technol. 35, 70–76 (2011).

    Google Scholar 

  41. 41.

    Bravery, C. A. et al. Potency assay development for cellular therapy products: an ISCT review of the requirements and experiences in the industry. Cytotherapy 15, 9–19 (2013).

    PubMed  Google Scholar 

  42. 42.

    Johnston, N., Schenck-Gustafsson, K. & Lagerqvist, B. Are we using cardiovascular medications and coronary angiography appropriately in men and women with chest pain? Eur. Heart J. 32, 1331–1336 (2011).

    PubMed  Google Scholar 

  43. 43.

    Cheng, K. et al. Brief report: mechanism of extravasation of infused stem cells. Stem Cells 30, 2835–2842 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Suzuki, G. et al. Global intracoronary infusion of allogeneic cardiosphere-derived cells improves ventricular function and stimulates endogenous myocyte regeneration throughout the heart in swine with hibernating myocardium. PLoS ONE 9, e113009 (2014).

    PubMed  PubMed Central  Google Scholar 

  45. 45.

    Tseliou, E. et al. Widespread myocardial delivery of heart-derived stem cells by nonocclusive triple-vessel intracoronary infusion in porcine ischemic cardiomyopathy: superior attenuation of adverse remodeling documented by magnetic resonance imaging and histology. PLoS ONE 11, e0144523 (2016).

    PubMed  PubMed Central  Google Scholar 

  46. 46.

    Golpanian, S. et al. Concise review: review and perspective of cell dosage and routes of administration from preclinical and clinical studies of stem cell therapy for heart disease. Stem Cells Transl. Med. 5, 186–191 (2016).

    PubMed  Google Scholar 

  47. 47.

    Losordo, D. W. et al. Intramyocardial, autologous CD34+ cell therapy for refractory angina. Circ. Res. 109, 428–436 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Oh, H. Cell therapy trials in congenital heart disease. Circ. Res. 120, 1353–1366 (2017).

    CAS  PubMed  Google Scholar 

  49. 49.

    Takehara, N. et al. The ALCADIA (Autologous Human Cardiac-Derived Stem Cell to Treat Ischemic Cardiomyopathy) trial. Circulation 126, 2776–2799 (2012).

    Google Scholar 

  50. 50.

    Fox, I. J. et al. Stem cell therapy. Use of differentiated pluripotent stem cells as replacement therapy for treating disease. Science 345, 1247391 (2014).

    PubMed  PubMed Central  Google Scholar 

  51. 51.

    Amariglio, N. et al. Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Med. 6, e1000029 (2009).

    PubMed  PubMed Central  Google Scholar 

  52. 52.

    Berkowitz, A. L. et al. Glioproliferative lesion of the spinal cord as a complication of “stem-cell tourism”. N. Engl. J. Med. 375, 196–198 (2016).

    PubMed  Google Scholar 

  53. 53.

    Thirabanjasak, D., Tantiwongse, K. & Thorner, P. S. Angiomyeloproliferative lesions following autologous stem cell therapy. J. Am. Soc. Nephrol. 21, 1218–1222 (2010).

    PubMed  PubMed Central  Google Scholar 

  54. 54.

    Malliaras, K. et al. Safety and efficacy of allogeneic cell therapy in infarcted rats transplanted with mismatched cardiosphere-derived cells. Circulation 125, 100–112 (2012).

    CAS  PubMed  Google Scholar 

  55. 55.

    Schu, S. et al. Immunogenicity of allogeneic mesenchymal stem cells. J. Cell. Mol. Med. 16, 2094–2103 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Al-Daccak, R. & Charron, D. Allogenic benefit in stem cell therapy: cardiac repair and regeneration. Tissue Antigens 86, 155–162 (2015).

    CAS  PubMed  Google Scholar 

  57. 57.

    Smith, R. R., Barile, L., Messina, E. & Marban, E. Stem cells in the heart: what’s the buzz all about? Part 2: arrhythmic risks and clinical studies. Heart Rhythm. 5, 880–887 (2008).

    PubMed  PubMed Central  Google Scholar 

  58. 58.

    Miyagawa, S. et al. Phase I clinical trial of autologous stem cell–sheet transplantation therapy for treating cardiomyopathy. J. Am. Heart Assoc. 6, e003918 (2017).

    PubMed  PubMed Central  Google Scholar 

  59. 59.

    Smith, R. R. et al. Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation 115, 896–908 (2007).

    PubMed  Google Scholar 

  60. 60.

    Sanz-Ruiz, R. & Fernández-Avilés, F. Autologous and allogeneic cardiac stem cell therapy for cardiovascular diseases. Pharmacol. Res. 127, 92–100 (2018).

    CAS  PubMed  Google Scholar 

  61. 61.

    White, A. J. et al. Intrinsic cardiac origin of human cardiosphere-derived cells. Eur. Heart J. 34, 68–75 (2013).

    CAS  PubMed  Google Scholar 

  62. 62.

    Davis, D. R. et al. Validation of the cardiosphere method to culture cardiac progenitor cells from myocardial tissue. PLoS ONE 4, e7195 (2009).

    PubMed  PubMed Central  Google Scholar 

  63. 63.

    Makkar, R. R. et al. Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet 379, 895–904 (2012).

    PubMed  PubMed Central  Google Scholar 

  64. 64.

    Ishigami, S. et al. Intracoronary cardiac progenitor cells in single ventricle physiology: the PERSEUS (cardiac progenitor cell infusion to treat univentricular heart disease) randomized phase 2 trial. Circ. Res. 120, 1162–1173 (2017).

    CAS  PubMed  Google Scholar 

  65. 65.

    Tarui, S. et al. Transcoronary infusion of cardiac progenitor cells in hypoplastic left heart syndrome: three-year follow-up of the Transcoronary Infusion of Cardiac Progenitor Cells in Patients with Single-Ventricle Physiology (TICAP) trial. J. Thorac. Cardiovasc. Surg. 150, 1198–1207 (2015).

    PubMed  Google Scholar 

  66. 66.

    Chimenti, I. et al. Relative roles of direct regeneration versus paracrine effects of human cardiosphere-derived cells transplanted into infarcted mice. Circ. Res. 106, 971–980 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Malliaras, K. et al. Stimulation of endogenous cardioblasts by exogenous cell therapy after myocardial infarction. EMBO Mol. Med. 6, 760–777 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Sanz-Ruiz, R. & Fernandez-Aviles, F. Autologous and allogeneic cardiac stem cell therapy for cardiovascular diseases. Pharmacol. Res. 127, 92–100 (2017).

    PubMed  Google Scholar 

  69. 69.

    Malliaras, K. et al. Validation of contrast-enhanced magnetic resonance imaging to monitor regenerative efficacy after cell therapy in a porcine model of convalescent myocardial infarction. Circulation 128, 2764–2775 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Reich, H. et al. Repeated transplantation of allogeneic cardiosphere-derived cells boosts therapeutic benefits without immune sensitization in a rat model of myocardial infarction. J. Heart Lung Transplant. 35, 1348–1357 (2016).

    PubMed  Google Scholar 

  71. 71.

    Chakravarty, T. et al. TCT-820 multivessel intracoronary infusion of allogeneic cardiosphere derived cells in dilated cardiomyopathy: long term outcomes of the Dilated Cardiomyopathy Intervention with Allogeneic Myocardially-Regenerative Cells (DYNAMIC trial). J. Am. Coll. Cardiol. 68, B332 (2016).

    Google Scholar 

  72. 72.

    Ibrahim, A. G., Cheng, K. & Marban, E. Exosomes as critical agents of cardiac regeneration triggered by cell therapy. Stem Cell Rep. 2, 606–619 (2014).

    CAS  Google Scholar 

  73. 73.

    Ibrahim, A. & Marban, E. Exosomes: fundamental biology and roles in cardiovascular physiology. Annu. Rev. Physiol. 78, 67–83 (2016).

    CAS  PubMed  Google Scholar 

  74. 74.

    Wang, Y. et al. Exosomes/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte apoptosis in the ischemic myocardium. Int. J. Cardiol. 192, 61–69 (2015).

    PubMed  PubMed Central  Google Scholar 

  75. 75.

    Kervadec, A. et al. Cardiovascular progenitor-derived extracellular vesicles recapitulate the beneficial effects of their parent cells in the treatment of chronic heart failure. J. Heart Lung Transplant. 35, 795–807 (2016).

    PubMed  Google Scholar 

  76. 76.

    Khan, M. et al. Embryonic stem cell-derived exosomes promote endogenous repair mechanisms and enhance cardiac function following myocardial infarction. Circ. Res. 117, 52–64 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Cambier, L. et al. Y RNA fragment in extracellular vesicles confers cardioprotection via modulation of IL-10 expression and secretion. EMBO Mol. Med. 9, 337–352 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Marban, E. The secret life of exosomes: what bees can teach us about next-generation therapeutics. J. Am. Coll. Cardiol. 71, 193–200 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Aminzadeh, M. A. et al. Exosome-mediated benefits of cell therapy in mouse and human models of Duchenne muscular dystrophy. Stem Cell Rep. 10, 942–955 (2018).

    CAS  Google Scholar 

  80. 80.

    Gallet, R. et al. Exosomes secreted by cardiosphere-derived cells reduce scarring, attenuate adverse remodelling, and improve function in acute and chronic porcine myocardial infarction. Eur. Heart J. 38, 201–211 (2017).

    CAS  PubMed  Google Scholar 

  81. 81.

    Funakoshi, S. et al. Enhanced engraftment, proliferation, and therapeutic potential in heart using optimized human iPSC-derived cardiomyocytes. Sci. Rep. 6, 19111 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Akers, J. C. et al. Optimizing preservation of extracellular vesicular miRNAs derived from clinical cerebrospinal fluid. Cancer Biomark. 17, 125–132 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Bosch, S. et al. Trehalose prevents aggregation of exosomes and cryodamage. Sci. Rep. 6, 36162 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Aminzadeh, M. A. et al. Reversal of cardiac and skeletal manifestations of Duchenne muscular dystrophy by cardiosphere-derived cells and their exosomes in mdx dystrophic mice and in human Duchenne cardiomyocytes. Preprint at https://www.biorxiv.org/content/early/2017/04/20/128900 (2017).

  85. 85.

    Chen, K. H. et al. Intravenous administration of xenogenic adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes markedly reduced brain infarct volume and preserved neurological function in rat after acute ischemic stroke. Oncotarget 7, 74537–74556 (2016).

    PubMed  PubMed Central  Google Scholar 

  86. 86.

    Vandergriff, A. C. et al. Intravenous cardiac stem cell-derived exosomes ameliorate cardiac dysfunction in doxorubicin induced dilated cardiomyopathy. Stem Cells Int. 2015, 960926 (2015).

    PubMed  PubMed Central  Google Scholar 

  87. 87.

    Conlan, R. S., Pisano, S., Oliveira, M. I., Ferrari, M. & Mendes Pinto, I. Exosomes as reconfigurable therapeutic systems. Trends Mol. Med. 23, 636–650 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    de Couto, G. et al. Exosomal MicroRNA transfer into macrophages mediates cellular postconditioning. Circulation 136, 200–214 (2017).

    PubMed  PubMed Central  Google Scholar 

  89. 89.

    Aminzadeh, M. A. et al. Therapeutic efficacy of cardiosphere-derived cells in a transgenic mouse model of non-ischaemic dilated cardiomyopathy. Eur. Heart J. 36, 751–762 (2015).

    CAS  PubMed  Google Scholar 

  90. 90.

    Tseliou, E. et al. Cardiospheres reverse adverse remodeling in chronic rat myocardial infarction: roles of soluble endoglin and TGF-β signaling. Basic Res. Cardiol. 109, 443 (2014).

    PubMed  Google Scholar 

  91. 91.

    Lauden, L. et al. Allogenicity of human cardiac stem/progenitor cells orchestrated by programmed death ligand 1. Circ. Res. 112, 451–464 (2013).

    CAS  PubMed  Google Scholar 

  92. 92.

    Marban, E. Breakthroughs in cell therapy for heart disease: focus on cardiosphere-derived cells. Mayo Clin. Proc. 89, 850–858 (2014).

    PubMed  PubMed Central  Google Scholar 

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This work is supported by grants from the National Institutes of Health, the California Institute for Regenerative Medicine, the United States Department of Defense, and Coalition Duchenne. I thank A. Ibrahim for creating a first draft of Fig. 6a, and L. Marbán for a critical reading of the manuscript and for helpful suggestions.

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E.M. holds founder’s equity in, and serves as unpaid scientific advisor to, Capricor Inc.

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Marbán, E. A mechanistic roadmap for the clinical application of cardiac cell therapies. Nat Biomed Eng 2, 353–361 (2018). https://doi.org/10.1038/s41551-018-0216-z

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